Heterocycle substituted propenoic acid derivatives as NMDA antagonist

ABSTRACT

The present invention is new 3-(heterocyclic)-propenoic acid derivatives and pharmaceutical compositions thereof. These new 3-(heterocyclic)-propenoic acid derivatives are useful as NMDA antagonist.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional patent application of Ser. No.08/990,673, filed Dec. 15, 1997, now U.S. Pat. No. 5,981,553 which is acontinuation of application Ser. No. 08/809,442, filed Jul. 16, 1997,now abandoned, which is a continuation of application Ser. No.08/332,016, filed Oct. 31, 1994, now U.S. Pat. No. 5,563,157, which isincorporated herein by reference.

The present invention is directed to a new class of excitatory aminoacid antagonists and intermediates thereof. These new antagonists,heterocycle substituted propenoic acid derivatives, are useful as NMDA(N-methyl-D-aspartate) antagonists. They preferentially bind to thestrychnine-insensitive glycine binding site on the NMDA receptor complexassociated with the treatment of a number of disease states. Anotheraspect of the invention is directed to their use in treatment of anumber of diseases as well as to pharmaceutical compositions containingthese excitatory amino acid antagonists.

In accordance with the present invention, a new class of NMDAantagonists has been discovered which can be described by the formula:

wherein

Z is hydrogen or —CH₃;

X is represented by —OH, a physiologically acceptable ester, or aphysiologically acceptable amide;

Y is represented by —OH, a physiologically acceptable ester, or aphysiologically acceptable amide;

R₁ is represented by from 1 to 3 substituents independently chosen fromthe group: hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, —CF₃, or —OCF₃;

G is a radical chosen from the group

 wherein

R₂ is represented by from 1 to 2 substituents independently chosen fromthe group: hydrogen or C₁-C₄ alkyl;

R₃ is represented by from 1 to 2 substituents independently chosen fromthe group: hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen;

and pharmaceutically acceptable addition salts thereof.

As used in this application:

a) the term “C₁-C₄ alkyl” refers to a branched or straight chained alkylradical containing from 1-4 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, and the like;

b) the term “C₁-C₄ alkoxy” refers to a branched or straight chainedalkoxy radical containing from 1-4 carbon atoms, such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and the like;

c) the term “halogen” refers to a fluorine atom, a chlorine atom, abromine atom, or a iodine atom;

d) the term “physiologically acceptable ester” refers to any non-toxicester or any prodrug that allows the compounds of this application tofunction as NMDA antagonists: these physiologically acceptable estersmay be chosen from but are not limited to compounds wherein X and Y mayeach independently be represented by —OR₄, —OCH₂OR₄ or—O—(CH₂)_(p)—NR₅R₆; wherein R₄ is represented by C₁-C₄ alkyl, phenyl,substituted phenyl, or an phenylalkyl substituent, such as benzyl, inwhich the phenyl ring may be optionally substituted; p is 2 or 3; and R₅and R₆ are each independently represented by a C₁-C₄ alkyl or togetherwith the adjacent nitrogen atom to form a ring —CH₂—CH₂—Z—CH₂—CH₂—wherein Z is a bond, O, S, or NR₇ in which R₇ is hydrogen or C₁-C₄alkyl; such rings include but are not limited to piperidino, morpholino,thiomorpholino, piperazino, N-methylpiperazino, or pyrrolidino; and thepharmaceutically acceptable addition salts thereof;

e) the term “physiologically acceptable amide” refers to any non-toxicamide or any prodrug that allows the compounds of this application tofunction as NMDA antagonists: these physiologically acceptable amidesmay be chosen from, but are not limited to, compounds wherein X and Ymay each independently be represented by —NR₈R₉; wherein R₈ and R₉ areeach independently represented by hydrogen, phenyl, substituted phenyl,phenylalkyl, or a C₁-C₄ alkyl; or R₈ and R₉ are taken together with theadjacent nitrogen atom to form a ring —CH₂—CH₂—Z—CH₂—CH₂— wherein Z is abond, O, S, or NR₇ in which R₇ is hydrogen or C₁-C₄ alkyl; such ringsinclude but are not limited to piperidino, morpholino, thiomorpholino,piperazino, N-methylpiperazino, or pyrrolidino and the pharmaceuticallyacceptable addition salts thereof;

f) the designation

 refers to a thienyl or thiophene and it is understood that the radicalis attached at either the 2-position or 3-position, it is furtherunderstood that when the radical is attached at the 2-position thesubstituent or substituents represented by R can be attached in any ofthe 3, 4, or 5 positions, and that when the radical is attached at the3-position the substituent or substituents represented by R can beattached in any of the 2, 4, or 5 positions;

g) the designation

 refers to a furyl, furanyl, or furan and it is understood that theradical is attached at either the 2-position or the 3-position, it isfurther understood that when the radical is attached at the 2-positionthe substituent or substituents represented by R can be attached in anyof the 3, 4, or 5 positions, and that when the radical is attached atthe 3-position the substituent or substituents represented by R can beattached in any of the 2, 4, or 5 positions;

h) the designation “C(O)” refers to a carbonyl group of the formula:

i) the designation

 refers to a pyridine, pyridinyl, or pyridyl and it is understood thatthe radical can be attached at either the 2-position, 3-position, or4-position, it is further understood that when the radical is attachedat the 2-position the substituent or substituents represented by R canbe attached in any of the 3, 4, 5, or 6 positions, that when the radicalis attached at the 3-position the substituent or substituentsrepresented by R can be attached in any of the 2, 4, 5, or 6 positions,and that when the radical is attached at the 4-position the substituentor substituents represented by R can be attached in any of the 2, 3, 5,or 6 positions;

j) the designation “”

refers to a bond for which the stereochemistry is not designated;

k) the term “pharmaceutically acceptable addition salts” refers toeither an acid addition salt or a basic addition salt.

The expression “pharmaceutically acceptable acid addition salts” isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by Formula (I) or any of itsintermediates. Illustrative inorganic acids which form suitable saltsinclude hydrochloric, hydrobromic, sulfuric, and phosphoric acid andacid metal salts such as sodium monohydrogen orthophosphate, andpotassium hydrogen sulfate. Illustrative organic acids which formsuitable salts include the mono-, di-, and tricarboxylic acids.Illustrative of such acids are for example, acetic, glycolic, lactic,pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic,cinnamic, salicylic, 2-phenoxybenzoic, and sulfonic acids such asp-toluenesulfonic acid, methane sulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either a hydrated orsubstantially anhydrous form. In general, the acid addition salts ofthese compounds are soluble in water and various hydrophilic organicsolvents, and which in comparison to their free base forms, generallydemonstrate higher melting points.

The expression “pharmaceutically acceptable basic addition salts” isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds represented by the Formula (I) or any of itsintermediates. Illustrative bases which form suitable salts includealkali metals or alkaline-earth metals hydroxides such as, sodium,potassium, calcium, magnesium, or barium hydroxides; ammonia andaliphatic, cyclic, or aromatic organic amines such as methylamine,dimethylamine, trimethylamine,and picoline.

The compounds of Formula (I) exist as geometric isomers. Any referencein this application to one of the compounds of Formula (I) is meant toencompass either a specific geometrical isomer or a mixture of isomers.The specific isomers can be separated and recovered by techniques knownin the art such as chromatography, and selective crystallization.

Illustrative examples of compounds encompassed by the present inventioninclude:

(E)-2-Bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(Z)-2-Bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(E)-2-(Thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(Z)-2-(Thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(E)-2-(Thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(Z)-2-(Thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(E)-2-(Thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(Z)-2-(Thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(E)-2-(Thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(Z)-2-(Thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(E)-2-(Fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(Z)-2-(Fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(E)-2-(Fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(Z)-2-(Fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(E)-2-(Fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(Z)-2-(Fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester;

(E)-2-(Fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(Z)-2-(Fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid;

(E)-2-(Pyrid-4-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile;

(Z)-2-(Pyrid-4-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile;

(E)-2-(Pyrid-3-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile;

(Z)-2-(Pyrid-3-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile;

(E)-2-(Pyrid-2-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile;

(Z)-2-(Pyrid-2-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile;

(Z)-2-(Pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide;

(Z)-2-(Pyrid-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide;

(Z)-2-(Pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide;

(E)-2-(Thien-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(Z)-2-(Thien-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(E)-2-(Thien-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(Z)-2-(Thien-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(E)-2-(Fur-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(Z)-2-(Fur-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(E)-2-(Fur-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(Z)-2-(Fur-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(E)-2-(Pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(Z)-2-(Pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(E)-2-(Pyrid-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(Z)-2-(Pyrid-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(E)-2-(Pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid;

(Z)-2-(Pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid.

The compounds of Formula (I) can be prepared as described in ReactionScheme 1. All substituents, unless otherwise indicated, are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art.

As disclosed in Reaction Scheme 1, the compounds of Formula (I) can beprepared by submitting an appropriate indole (1) to a Wittig-typereaction to give an 2-bromo-3-(indol-3-yl)propenoic acid ester ofstructure (2), a Suzuki coupling reaction with an appropriatearylboronic acid, G-B(OH)₂, to give compound (3), and deprotection andfunctionalization to give a compound of Formula (I). In preparingcompounds of Formula (I) in which G is thienyl or furyl the methoddescribed in Reaction Scheme 1 is preferred.

In Reaction Scheme 1, step 1, an appropriate indole of structure (1) iscontacted with an appropriate organophosphorous ylid in a Wittig-typereaction to give an 2-bromo-3-(indol-3-yl)propenoic acid ester ofstructure (2).

An appropriate indole compound of structure (1) is one in which R₁, andZ are as desired in the final product of Formula (I), Pg₁ is X asdesired in the final product of formula (I) or gives rise afterdeprotection and functionalization as required to X as desired in thefinal product of Formula (I), and Pg₃ is a protecting group which isreadily removed to give a final product of Formula (I) or allows forselective deprotection and functionalization as may be required toincorporate X and Y desired in the final product of Formula (I).Appropriate indoles of structure (1) are readily prepared by methodswell known in the art, such as the Fischer indole synthesis,introduction of a 3-position carbonyl substituent, and protection of theindole nitrogen.

An appropriate organophosphorous ylid is one which converts the3-position carbonyl of an indole of structure (1) to an 2-bromopropenoicacid ester of structure (2) in which Pg₂ is Y as desired in the finalproduct of Formula (I) or gives rise after deprotection andfunctionalization as required to Y as desired in the final product ofFormula (I). An appropriate organophosphorous ylid is formed bycontacting an appropriate organophosphorous reagent, such as t-butyldiethylphosphonobromoacetate or ethyl diethylphosphonobromoacetate, witha suitable base, such as lithium diisopropylamide, sodium hydride,lithium bis(trimethylsilyl)amide or potassium t-butoxide. Appropriateorganophosphorous reagents and the use of appropriate organophosphorousreagents is well known and appreciated in the art.

For example, an appropriate organophosphorous reagent is contacted witha suitable base, such as lithium diisopropylamide, sodium hydride,lithium bis(trimethylsilyl)amide or potassium t-butoxide. The ylidformation is carried out in a suitable solvent, such as tetrahydrofuran,benzene, or diethyl ether. The ylid formation is generally carried outat a temperature of from −78° C. to ambient temperature. An appropriateorganophosphorous ylid is contacted with an appropriate indole ofstructure (1). The reaction is carried out in a suitable solvent, suchas tetrahydrofuran, benzene, or diethyl ether. Generally, the reactionis carried out in the same solvent used to form the appropriateorganophosphorous ylid. The reaction is carried out at temperatures offrom −78° C. to the reflux temperature of the solvent. The reactiongenerally requires from 1 hour to 48 hours. The product can be isolatedby techniques well known in the art, such as extraction and evaporation.The product can then be purified by techniques well known in the art,such as distillation, chromatography, or recrystallization.

In Reaction Scheme 1, step 2, an appropriate2-bromo-3-(indol-3-yl)propenoic acid ester of structure (2) is contactedwith an appropriate arylboronic acid in a Suzuki coupling to give acompound of structure (3). N. Miyaura et al., J. Org. Chem., 51,5467-5471 (1986); Y. Hoshino et al., Bull. Chem. Soc. Japan, 61,3008-3010 (1988); N. Miyaura et al., J. Am. Chem. Soc., 111, 314-321(1989); W. J. Thompson et al., J. Org. Chem., 53, 2052-2055 (1988); andT. I. Wallow and B. M. Novak, J. Org. Chem., 59, 5034-5037 (1994).

An appropriate arylboronic acid, G-B(OH)₂, is one in which G is asdesired in the final product of Formula (I). The preparation and use ofarylboronic acids is well known and appreciated in the art. W. J.Thompson and J Gaudino, J. Org. Chem., 49, 5237-5243 (1984). Arylboronicacids are frequently contaminated with their corresponding anhydrideswhich do not perform well in the Suzuki coupling. Material contaminatedby detrimental amounts of anhydride can be converted to thecorresponding acid by hydrolysis. The hydrolysis is performed, ifrequired, by briefly boiling in water and the arylboronic acid isrecovered by filtration.

For example, an appropriate 2-bromo-3-(indol-3-yl)propenoic acid esterof structure (2) is contacted with an appropriate arylboronic acid. TheSuzuki coupling reaction is performed in a suitable solvent, such astoluene or tetrahydrofuran. The reaction is performed using from about1.1 to about 3 molar equivalents of an appropriate arylboronic acid. Thereaction is carried out in the presence of from about 1 to about 3 molarequivalents of a suitable base, such as potassium carbonate, sodiumcarbonate. The coupling is performed using a suitable palladiumcatalyst, such as tetrakis(triphenylphosphine)palladium (0),bis(acetonitrile)palladium (II) chloride, palladium (II) chloride,palladium (II) acetoacetate, andtris(dibenzylidneacetone)dipalladium(0). The suitable palladium catalystchosen may be modified by the use of ligands, such astri(fur-2-yl)phosphine and tri(o-toluene)phosphine. V. Farina and B.Krishnan, J. Am. Chem. Soc., 113, 9586-9595 (1991). The coupling isperformed at a temperature ranging from 0° C. to the refluxingtemperature of the solvent. The coupling reactions depicted in ReactionScheme 1 generally require from 6 hours to 14 days. The product (3) ofthe coupling reaction can be isolated and purified using techniques wellknown in the art. These techniques include extraction, evaporation,chromatography and recrystallization.

In Reaction Scheme 1, step 3, the compound of structure (3) obtainedfrom the coupling reaction is deprotected and functionalized usingtechniques well known in the art to give compounds of Formula (I). Thesetechniques include hydrolysis of esters, selective hydrolysis of esters,transesterification, removal of indole protecting groups, amidation ofactivated ester leaving groups, and esterification of activated esterleaving groups. As is appreciated to one skilled in the art, in Scheme 1the number and order of deprotection, functionalization, and protectionsteps carried out will depend on the compound of Formula (I) which isdesired as the product of Scheme 1. The selection, use, and removal ofprotecting groups utilizing suitable protecting groups such as thosedescribed in Protecting Groups in Organic Synthesis by T. Greene,Wiley-Interscience (1981) is well known and appreciated in the art.

As is disclosed in Reaction Scheme 1, step 3, the compounds of Formula(I) can be prepared by submitting a compound (3) to an appropriatefunctionalization reaction which introduces the appropriatefunctionality at the 2-position of the indole nucleus and/or at the1-position of the propenoic acid thereby producing one of the desiredcompounds of Formula (I). In structure (3), Z, R₁, and G are as definedin Formula (I), Pg₃ is represented by an indole nitrogen protectinggroup, and Pg₁ and Pg₂ are each independently represented by groups suchas, C₁-C₄ alkyl, or other active ester leaving groups known in the art,physiologically acceptable ester, or physiologically acceptable amide.

The functionalization reactions can be carried out using techniques wellknown in the art. For example, ester functionalities can be added to the2-position of the indole nucleus and/or at the 1-position of thepropenoic acid utilizing a variety of esterification techniques. Onesuitable esterification technique comprises contacting the appropriatecompound of structure (3) in which Pg₁ and Pg₂ are C₁-C₄ alkyl functionswith an excess of an appropriate alcohol. An appropriate alcohol is onewhich gives rise to groups X and Y as desired in the final product ofFormula (I). The reaction is typically carried out in the presence of anexcess of a base such as potassium carbonate. The reaction is typicallycarried out at a temperature ranging from room temperature to reflux fora period of time ranging from 1 hour to 24 hours. After the reaction iscompleted, the desired product of Formula (I) can be recovered byorganic extraction and evaporation. It may then be purified by flashchromatography and recrystallization as is known in the art.

Amides can also be easily be prepared by contacting a compound ofstructure (3) in which Pg₁ and Pg₂ are C₁-C₄ alkyls with an excess ofammonia or a mono- or dialkylamine corresponding to X and Y desired inthe final product of Formula (I). The reaction is carried out at atemperature of from 0-100° C. for a period of time ranging from 1-48hours using the amine as solvent or in an inert solvent such astetrahydrofuran. The resulting amide derivatives of Formula I can thenbe isolated and purified by techniques known in the art.

As is readily apparent to those skilled in the art, if X and Y are notboth represented by the same function in the final product, then it willbe necessary to carry out deprotection and functionalization reactionsin a sequential manner utilizing suitable protecting groups such asthose described in Protecting Groups in Organic Synthesis, T. Greene.This can be done utilizing techniques known to those skilled in the art;D. B. Bryan et al, J. Am. Chem. Soc., 99, 2353 (1977); E. Wuensch,Methoden der Organischen Chemie (Houben-Weyl), E. Mueller, Ed., GeorgeTheime Verlag, Stuttgart, 1974, Vol. 15; M. G. Saulnierand and G. W.Gribble, J. Org. Chem., 47, 2810 (1982); Y. Egawa et al, Chem. Pharm.Bull. 7, 896 (1963); R. Adams and L. H. Ulich, J. Am. Chem. Soc., 42,599 (1920); and J Szmuszkoviocz, J. Org. Chem., 29, 834 (1964).

The formation and use of active ester leaving groups used infunctionalizations reactions is well known and appreciated in the art.Active ester leaving groups include but are not limited to anhydrides,mixed anhydrides, acid chlorides, acid bromides, 1-hydroxybenzotriazoleesters, 1-hydroxysuccinimide esters, or the activated intermediatesformed in the presence of coupling reagents, such asdicyclohexylcarbodiimide, 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide,and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolone. Active ester leavinggroups may be prepared and isolated before their use or may be preparedand used without isolation to form physiologically acceptable esters orphysiologically acceptable amides.

For example, a compound of Formula (I) in which Y is a physiologicallyacceptable amide and X is a physiologically acceptable ester or —OH canbe prepared from a compound of structure (3) in which Pg₂ is t-butyl andPg₁ is a physiologically acceptable ester other than t-butyl or ahydrolyzable ester. Selective removal of the t-butyl group gives acompound of structure (3) in which Pg₂ is —OH and Pg₁ is aphysiologically acceptable ester other than t-butyl or a hydrolyzableester which can be amidated through the formation of an activated esterleaving group followed by the addition of an suitable amine as is wellknown in the art. A suitable amine is one which gives a physiologicallyacceptable amide, Y, as is desired in the final product of Formula (I).Suitable amines include but are not limited to methylamine,dimethylamine, ethylamine, diethylamine, propylamine, butylamine,aniline, 4-chloroaniline, N-methylaniline, benzylamine, phenethylamine,morpholine, piperazine, piperidine, N-methylpiperazine, thiomorpholine,pyrrolidine, and N-methylbenzylamine. Formation of an active esterleaving group requires protection of the indole NH using a suitableprotecting group, such as benzenesulfonyl, p-toluenesulfonyl,trimethylsilyl, trimethylsilylethoxymethyl, and the like. Furtherfunctionalization or hydrolysis gives a compound of Formula (I) in whichY is a physiologically acceptable amide and X is a physiologicallyacceptable ester or —OH. After the functionalization removal of theindole NH protecting group gives a compound of Formula (I).

Similarly, a compound of Formula (I) in which X is a physiologicallyacceptable amide and Y is a physiologically acceptable ester or —OH canbe prepared from a compound of structure (3) in which Pg₁ is t-butyl andPg₂ is a physiologically acceptable ester other than t-butyl or ahydrolyzable ester.

The compounds of Formula (I) in which X and Y are —OH can be preparedfrom a compound of structure (3) in which Pg₁ and Pg₂ are C₁-C₄ alkoxy,or an activated ester leaving group by deprotection using a molar excessof a suitable reagent, such as lithium hydroxide, sodium hydroxide,potassium hydroxide, sodium bicarbonate, sodium carbonate, or potassiumcarbonate with lithium hydroxide, sodium hydroxide, potassium hydroxidebeing preferred and lithium hydroxide being most preferred. Thesedeprotections are carried out in a suitable solvent, such as mixtures oftetrahydrofuran and water, or water. The reaction is typically carriedout at a temperature ranging from room temperature to reflux for aperiod of time ranging from 1 hour to 24 hours. After the reaction iscompleted, the desired product of Formula (I) can be recovered bytechniques well known in the art, such as evaporation, precipitation byadjustment of the pH of the solution with a suitable acid such ashydrochloric acid, sodium bisulfate, potassium bisulfate, acetic acid,etc., extraction, and recrystallization.

Alternately, some of the compounds of Formula (I) can be prepared asdescribed in Reaction Scheme 2. All substituents, unless otherwiseindicated, are previously defined. The reagents and starting materialsare readily available to one of ordinary skill in the art.

As disclosed in Reaction Scheme 2, the compounds of Formula (I) can beprepared by submitting an appropriate indole (1) to a condensationreaction to give an 2-aryl-3-(indol-3-yl)propenonitrile of structure(4), hydrolysis to give compound (5), and deprotection and/orfunctionalization to give a compound of formula (I). In preparingcompounds of Formula (I) in which G is pyridyl the method described inreaction Scheme 2 is preferred.

In Reaction Scheme 2, step 1, an appropriate indole of structure (1) iscontacted with an appropriate arylacetonitrile in a condensationreaction to give a 2-aryl-3-(indol-3-yl)propenonitrile of structure (4).

An appropriate indole compound of structure (1) is one in which R₁, andZ are as desired in the final product of Formula (I), Pg₁ is X asdesired in the final product of formula (I) or gives rise afterdeprotection and functionalization as required to X as desired in thefinal product of Formula (I), and Pg₃ is hydrogen or a protecting groupwhich is readily removed to give a final product of Formula (I) orallows for selective deprotection and functionalization as may berequired to incorporate X and Y desired in the final product of Formula(I). Appropriate indoles of structure (1) are readily prepared bymethods well known in the art, such as the Fischer indole synthesis,introduction of a 3-position carbonyl substituent, and if required,protection of the indole nitrogen.

An appropriate arylacetonitrile, G—CH₂—CN, is one in which G is asdesired in the final product of Formula (I).

For example, an appropriate indole of structure (1) is contacted with anappropriate arylacetonitrile. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, ethanol, or methanol. The reaction iscarried out using a suitable base, such as piperidine, triethylamine,sodium hydride, or sodium carbonate. The reaction is generally carriedout at temperatures of from ambient temperature to the refluxingtemperature of the solvent. The reaction generally requires from 1 hourto 120 hours. The product can be isolated by techniques well known inthe art, such as extraction and evaporation. The product can then bepurified by techniques well known in the art, such as distillation,chromatography, or recrystallization.

In Reaction Scheme 2, step 2, an appropriate2-aryl-3-(indol-3-yl)propenonitrile of structure (4) is hydrolyzed togive a compound of structure (5) in which Y₁ is —OH or —NH₂. It isunderstood that such hydrolyses may be carried out in a number of stepsthrough intermediates, such as imides.

In Reaction Scheme 2, step 3, the compound of structure (5) obtainedfrom the hydrolysis reaction may be optionally protected, deprotected,and functionalized using techniques well known in the art and describedin Reaction Scheme 1, step 3, to give compounds of Formula (I). Thesetechniques include formation of esters to give a compound of structure(3), hydrolysis of esters, selective hydrolysis of esters,transesterification, removal of indole protecting groups, amidation ofactivated ester leaving groups, and esterification of activated esterleaving groups.

The following preparations represent typical procedures for preparingstarting materials used in the examples. The following examples presenttypical syntheses as described in Reaction Scheme 1, and Reaction Scheme2. These preparations and examples are understood to be illustrativeonly and are not intended to limit the scope of the invention in anyway. As used in the following preparations and examples, the followingterms have the meanings indicated: “kg” refers to kilograms, “g” refersto grams, “mg” refers to milligrams, “mol” refers to moles, “mmol”refers to millimoles, “L” refers to liters, “mL” refers to milliliters,“°C.” refers to degrees Celsius, “M” refers to molar, “mp” refers tomelting point, “dec” refers to decomposition.

PREPARATION 1.13-Formyl-1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindole

Combine 3,5-dichlorophenylhydrazine (300 g) and ethanol (2 L). Add ethylpyruvate (153.6 mL) and sulfuric acid (25 mL). After 3 hours, evaporatein vacuo to obtain a residue. Cover the residue with ethyl acetate andwater. Add solid sodium bicarbonate until the aqueous layer isneutralized. Separate the layers and extract the aqueous layer withethyl acetate. Combine the organic layers, dry over MgSO₄, filter, andevaporate in vacuo to give ethyl pyruvate-3,5-dichlorophenylhydrazone.

Combine ethyl pyruvate-3,5-dichlorophenylhydrazone (100 g) andpolyphosphoric acid (2 kg). Heat on a stream bath. After 5 hours, stopthe heating and slowly add ice (100 g) to thin the solution. Pour thereaction mixture onto ice to give an aqueous suspension. Extract theaqueous suspension three times with ethyl acetate. Combine the organiclayers, dry over MgSO₄, filter, and evaporate in vacuo to give a solid.Triturate the solid with diethyl ether, filter, and dry to give2-carboethoxy-4,6-dichloroindole.

Combine 2-carboethoxy-4,6-dichloroindole (20.0 g, 0.077 mol), anddimethylformamide (9.0 mL, 0.117 mol) in dichloroethane (100 mL). Addphosphoryl chloride (18.0 g, 0.117 mmol). Heat to reflux. After 3.5hours, cool the reaction mixture to ambient temperature to obtain asolid. Collect the solid by filtration, rinse with water. Combine thesolid with aqueous 1 M sodium acetate solution and stir. After 1 hour,filter, rinse with water, and dry to give3-formyl-2-carboethoxy-4,6-dichloroindole.

Combine 3-formyl-2-carboethoxy-4,6-dichloroindole (46.3 g. 162 mmol) andanhydrous potassium carbonate (44.9 g, 325 mmol) in dimethylformamide(600 mL). Add p-toluenesulfonyl chloride (42.9 g, 225 mmol). After 18hours, pour the reaction mixture into water (3 L) and stir to give asolid. Filter, rinse with water and diethyl ether, and recrystallizefrom acetonitrile/dichloroethane to give the title compound.

PREPARATION 1.23-Formyl-1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindole

Combine 2-carboethoxy-4,6-dichloroindole (10.0 g, 0.039 mol), anddimethylformamide (4.5 mL, 0.057 mol) in dichloroethane (20 mL). Addphosphoryl chloride (8.9 g, 0.058 mmol). Heat to 80° C. After 18 hours,cool the reaction mixture to ambient temperature and combine withaqueous 1 M sodium acetate solution and stir. After 18 hours, filter,rinse with water, and dry to give3-formyl-2-carboethoxy-4,6-dichloroindole.

React 3-formyl-2-carboethoxy-4,6-dichloroindole with p-toluenesulfonylchloride as describe in Preparation 1.1 to give the title compound.

PREPARATION 2 3-Acetyl-1-p-toluenesulfonyl-2-carboethoxy-indole

Prepare by the method of Preparation 1.1. using3-acetyl-2-carboethoxy-indole, Y. Murakami, et al., Heterocycles 22,241-244 (1984) and Y. Murakami, et al., Heterocycles 14, 1939-1941(1980) and p-toluenesulfonyl chloride to give the title compound.

PREPARATION 3 Furan-2-boronic acid

According to the method of M. J. Arco et al., J. Org. Chem., 412075-2083 (1976) combine furan (10 g, 147 mmol) and tetrahydrofuran ((50mL). Cool to −30° C. Add a solution of n-butyl lithium (59 mL, 2.5 M inhexane, 147 mmol). After the addition is complete, warm the reactionmixture to −15° C. After 4 hours, add triisopropylborate (56.4 g, 300mmol) and warm to ambient temperature. After 24 hours, partition thereaction mixture between 0.5 M aqueous hydrochloric acid solution anddiethyl ether. Separate the organic layer, dry over MgSO4, filter, anddry in vacuo to give a residue. Recrystallize the residue from water,filter, and dry to give the title compound.

PREPARATION 4 Furan-3-boronic acid

Cool a solution of n-butyl lithium (25.4 mL, 2.5 M in hexane, 63.6 mmol)to −78° C. Add a solution 3-bromofuran (7.8 g, 53 mmol) intetrahydrofuran (20 mL). After 10 minutes, add triisopropylborate (20 g,106 mmol) and warm to ambient temperature. After 24 hours, partition thereaction mixture between 0.5 M aqueous hydrochloric acid solution anddiethyl ether. Separate the organic layer, dry over MgSO₄, filter, anddry in vacuo to give a residue. Recrystallize the residue from water,filter, and dry to give the title compound.

PREPARATION 5 t-Butyl diethylphosphonobromoacetate

Combine sodium hydroxide (65 g, 1.6 mol) and water (195 mL). Cool to−10° C. Add dropwise, bromine (42 mL, 0.81 mol) at such a rate that thetemperature of the reaction does not rise above 0° C. Add t-butyldiethylphosphonoacetate (46.5 g, 184 mmol) at such a rate that thetemperature of the reaction does not rise above 0° C. After 90 minutes,extract the reaction mixture three times with chloroform. Combine theorganic layers and extract with water, dry over MgSO₄, filter, andevaporate in vacuo to give t-butyl diethylphosphonodibromoacetate.

Combine t-butyl diethylphosphonodibromoacetate (75.6 g, 184 mmol) andisopropanol (190 mL). Cool to 0° C. Add a solution of tin (II) chloride(33.2 g, 175 mmol) in water (190 mL). After the addition is complete,warm to ambient temperature. After 1 hour, extract the reaction mixturethree times with chloroform. Combine the organic layers and extract withwater, dry over MgSO₄, filter, and evaporate in vacuo to give the titlecompound.

PREPARATION 6 (E) and(Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester

Combine t-butyl diethylphosphonobromoacetate (45.4 g, 137 mmol) andtetrahydrofuran (550 mL). Cool to −78° C.

Add dropwise a solution of lithium bis(trimethylsilyl)amide (137 mL, 1.0M in tetrahydrofuran, 137 mmol). Add, portionwise over 30 minutes,3-formyl-1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindole (38.4 g,87.2 mmol). After the addition is complete, warm to ambient temperature.After 18 hours, add water and evaporate in vacuo to remove thetetrahydrofuran. Extract with dichloromethane. Dry the organic layerover MgSO₄, filter, and evaporate in vacuo to give a residue.Recrystallize the powder from ethyl acetate/cyclohexane, filter, and dryto give the (Z)-isomer: mp 131-132° C. ¹H NMR (CDCl₃) δ 8.21 (s,1H),7.95 (m, 3H), 7.30 (m, 3H), 4.42 (q, 2H, J=7.2 Hz), 2.41 (s, 3H), 1.56(s, 9H), 1.36 (t, 3H, J=7.15 Hz). Elemental Analysis calculated forC₂₅H₂₄BrCl₂NO₆S: C, 48.64; H, 3.92; N, 2.26. Found: C, 48.44; H, 3.90;N, 2.22.

Chromatograph a mixture of (E) and (Z)-isomers on silica gel. Evaporatethe early eluting fractions to give a residue enriched in the(E)-isomer. Recrystallize the residue from diethyl ether/pentane andcool to −20° C. to give the (E)-isomer. ¹H NMR (CDCl₃) δ 7.99 (d, 1H,J=1.7 Hz), 7.96 (d, 2H, J=8.7 Hz), 7.50 (s, 1H), 7.33 (d, 2H, J=8.7 Hz),7.27 (d, 1H, J=1.7 Hz), 4.42 (q, 2H, J=7.2 Hz), 2.42 (s, 3H), 1.39 (t,3H, J=7.2 Hz), 1.00 (s, 9H).

PREPARATION 7(Z)-2-bromo-3-methyl-3-(1-p-toluenesulfonyl-2-carboethoxy-indol-3-yl)propenoicacid, t-butyl ester

Prepare by the method of Preparation 6 using3-acetyl-1-p-toluenesulfonyl-2-carboethoxy-indole to give the titlecompound.

EXAMPLE 1 Preparation of(E)-2-(Thien-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid 1.1 Synthesis of(E)-2-(Thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester

Combine tris(dibenzylideneacetone)dipalladium(0) (204 mg, 0.223 mmol)and tri-(fur-2-yl)phosphine (413 mg, 1.78 mmol) in tetrahydrofuran (60mL). After 5 minutes, add(Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester (1.85 g, 3.0 mmol), thiophene-3-boronic acid (1.16g, 9.1 mmol), and powdered potassium carbonate (1.27 g, 9.2 mmol). Heatto 60° C. After 6 days, add thiophene-3-boronic acid (744 mg, 30 5.8mmol),tri-(fur-2-yl)phosphine (206 mg, 0.887 mmol),tris(dibenzylideneacetone)dipalladium(0) (102 mg, 0.111 mmol), andpowdered Potassium carbonate (800 mg, 5.80 mmol). After 3 more days,dilute the reaction mixture with cyclohexane (60 mL) and chromatographon silica gel eluting with 3/1 cyclohexane/ether to give the titlecompound. ¹H NMR (CDCl₃) δ 7.94 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.4Hz), 7.72 (s, 1H), 7.26 (d, 2H, J=8.0 Hz), 7.24 (d, 1H, J=1.7 Hz), 7.03(d, 1H, J=4.4 Hz), 7.02 (d, 1H, J=1.5 Hz), 6.77 (dd, 1H, J=4.7, 1.6 Hz),4.20 (q, 2H, J=7.15 Hz), 2.40 (s, 3H), 1.55 (s, 9H), 1.28 (t, 3H, J=7.15Hz).

1.2 Synthesis of(E)-2-(Thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid

Combine(E)-2-(thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester and trifluoroacetic acid (10 mL). After 45 min,evaporate in vacuo to obtain a residue. Dissolve the residue in ethylacetate and extract with water. Evaporate the organic layer in vacuo toobtain a residue. Triturate with pentane containing a small amount ofether to give a solid. Recrystallize the solid from cyclohexane/ethylacetate, filter, and dry to give the title compound: mp 197-200° C.(dec); ¹H NMR (CDCl₃) δ 8.00 (s, 1H), 7.95 (d, 1H, J=1.7 Hz), 7.74 (d,2H, J=8.5 Hz), 7.27 (d, 2H, J=8.5 Hz), 7.25 (d, 1H, J=1.7 Hz), 7.08 (d,1H, J=2.8 Hz), 7.08 (d, 1H, J=3.6 Hz), 6.81 (dd, 1H, J=3.6, 2.8 Hz),4.22 (q, 2H, J=7.2 Hz), 2.40 (s, 3H), 1.28 (t, 3H, J=7.2 Hz); ¹H NMR(DMSO-d₆) δ 13.07 (br s, 1H), 7.88 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.4Hz), 7.66 (s, 1H), 7.57 (d, 1H, J=1.7 Hz), 7.44 (d, H, J=8.4 Hz), 7.27(dd, 1H, J=5.0, 2.9 Hz), 7.09 (dd, 1H, J=2.9, 1.2 Hz), 6.63 (dd, 1H,J=5.0, 1.2 Hz), 4.11 (q, 2H, J=7.1 Hz), 2.36 (s, 3H), 1.14 (t, 3H, J=7.1Hz). Elemental Analysis calculated for C₂₅H₁₉Cl₂NO₆S₂: C, 53.20; H,3.39; N, 2.48. Found: C, 52.80; H, 3.19; N, 2.29.

1.3 Synthesis of(E)-2-(Thien-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid

Combine(E)-2-(thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid (1.15 g, 2.03 mmol) and lithium hydroxide hydrate (288 mg, 6.86mmol) in 1/1 tetrahydrofuran/water (22 mL). Heat to reflux. After 4hours, cool to ambient temperature, evaporate in vacuo to remove most ofthe tetrahydrofuran, dilute with water, and acidify using an aqueoussodium bisulfate solution. Extract with ethyl acetate. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a solid.Recrystallize the solid from cyclohexane/ethyl acetate/acetone, filter,and dry in vacuo with heat to give the title compound: mp 228-232° C.(dec). ¹H NMR (DMSO-d₆) δ 13.3 (br s, 1H), 12.8 (br s, 1H), 12.24 (s,1H), 8.01 (s, 1H), 7.37 (d, 1H, J=1.7 Hz), 7.20 (dd, 1H, J=5.0, 3.0 Hz),7.12 (d, 1H, J=1.7 Hz), 7.03 (dd, 1H, J=3.0, 1.2 Hz), 6.66 (dd, 1H,J=5.0, 1.2 Hz). Elemental Analysis calculated for C₁₆H₉Cl₂NO₄S: C,50.28; H, 2.37; N, 3.66. Found: C, 50.01; H, 2.56; N, 3.57.

EXAMPLE 2 Preparation of(E)-2-(Thien-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid 2.1 Synthesis of(E)-2-(Thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester

Combine tris(dibenzylideneacetone)dipalladium(0) (412 mg, 0.450 mmol)and tri-(fur-2-yl)phosphine (837 mg, 3.60 mmol) in tetrahydrofuran (60mL). After 5 minutes, add(Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester (1.85 g, 3.0 mmol), thiophene-2-boronic acid (1.12g, 9.20 mmol), and powdered potassium carbonate (1.27 g, 9.2 mmol). Heatto 60° C. After 8 days, dilute the reaction mixture with cyclohexane(120 mL) and chromatograph on silica gel eluting with 3/1cyclohexane/ether to give the title compound. ¹H NMR (CDCl₃) δ 7.97 (d,1H, J=1.7 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.64 (s, 1H), 7.27 (d, 2H, J=8.5Hz), 7.23 (d, 1H, J=1.7 Hz), 7.16 (dd, 1H, J=5.1, 1.2 Hz), 6.83 (dd, 1H,J=3.7, 1.2 Hz), 6.75 (dd, 1H, J=5.1, 3.7 Hz), 4.24 (q, 2H, J=7.1 Hz),2.39 (s, 3H), 1.57 (s, 9H), 1.26 (t, 3H, J=7.1 Hz).

2.2 Synthesis of(E)-2-(Thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid

Combine(E)-2-(thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester and formic acid (96%, 20 mL). After 2 hours,evaporate in vacuo to obtain a residue. Triturate with pentanecontaining a small amount of diethyl ether to obtain a solid.Recrystallize the solid from cyclohexane/ethyl acetate/acetone, filter,and dry to give the title compound: mp 184-187° C. (dec). ¹H NMR(DMSO-d₆) δ 13.2 (br s, 1H), 7.92 (d, 1H, J=1.7 Hz), 7.80 (d, 2H, J=8.4Hz), 7.60 (s, 1H), 7.57 (d, 1H, J=1.7 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.40(dd, 1H, J=4.7, 1.5 Hz), 6.84-6.8 (m, 2H), 4.14 (q, 2H, J=7.1 Hz), 2.37(s, 3H), 1.13 (t, 3H, J=7.1 Hz). Elemental Analysis calculated forC₂₅H₁₉Cl₂NO₆S₂: C, 53.20; H, 3.39; N, 2.48. Found: C, 53.30; H, 3.40; N,2.41.

2.3 Synthesis of(E)-2-(Thien-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid

Combine(E)-2-(thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid (1.24 g, 2.20 mmol) and lithium hydroxide hydrate (313 mg, 7.46mmol) in 1/1 tetrahydrofuran/water (24 mL). Heat to reflux. After 4hours, cool to ambient temperature, evaporate in vacuo to remove most ofthe tetrahydrofuran, dilute with water, and acidify using an aqueoussodium bisulfate solution. Extract with ethyl acetate. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a solid.Recrystallize the solid from cyclohexane/ethyl acetate/acetone, filter,and dry to give the title compound: mp 239-244° C. (dec). ¹H NMR(DMSO-d₆) δ 7.92 (s, 1H), 7.38 (d, 1H, J=1.7 Hz), 7.28 (dd, 1H, J=5.1,1.2 Hz), 7.12 (d, 1H, J=1.7 Hz), 6.87 (dd, 1H, J=3.7, 1.2 Hz), 6.77 (dd,1H, J=5.1, 3.7 Hz). Elemental Analysis calculated for C₁₆H₉Cl₂NO₄S: C,50.28; H, 2.37; N, 3.66. Found: C, 50.31; H, 2.58; N, 3.51.

EXAMPLE 3 Preparation of(E)-2-(Fur-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid 3.1 Synthesis of(E)-2-(Fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester

Combine(Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester (1.00 g, 1.6 mmol), furan-2-boronic acid (0.27 g,2.4 mmol), and cesium carbonate (1.00 g, 3.2 mmol) in toluene (15 mL).Sparge with nitrogen for 15 minutes. Addtetrakis(triphenylphosphine)palladium(0) (50 mg). Heat to 90° C. After 3days, partition the reaction mixture between ethyl acetate and water.Separate the layers. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a reside. Chromatograph the residue on silicagel eluting with 15% diethyl ether/hexane to give the title compound.

3.2 Synthesis of(E)-2-(Fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid

Combine(E)-2-(fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester (112 mg, 0.19 mmol) and trifluoroacetic acid (2 mL)in dichloromethane (5 mL). After 2 hours, evaporate in vacuo, adddichloromethane and evaporate in vacuo to give the title compound.

3.3 Synthesis of (E)-2-(Fur-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylicacid)propenoic acid

Combine(E)-2-(fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid (0.1 g, 0.18 mmol) and an aqueous solution of lithium hydroxide (2mL, 1 M in water, 2 mmol) in tetrahydrofuran (2 mL). Heat to reflux.After 24 hours, cool to ambient temperature, dilute with water, andacidify using aqueous hydrochloric acid solution to give a solid.Filter, and dry in vacuo to give the title compound: mp 237-239° C.(dec). ¹H NMR (DMSO-d₆) δ 13.3 (bs, 1H), 12.95 (bs, 1H), 12.32 (s, 1H),7.90 (s, 1H), 7.40 (d, 1H, J=1.8 Hz), 7.29 (dd, 1H, J=1.7, 0.6 Hz), 7.12(d, 1H, J=1.8 Hz), 6.43 (dm, 1H, J=3.4 Hz), 6.31 (dd, 1H, J=3.4, 1.8Hz).

EXAMPLE 4 Preparation of(E)-2-(Fur-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid 4.1 Synthesis of(E)-2-(Fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester

Prepare by a method similar to Example 3.1 using furan-3-boronic acid togive the title compound.

4.2 Synthesis of(E)-2-(Fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid

Prepare by a method similar to Example 3.2 using(E)-2-(fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid, t-butyl ester to give the title compound.

4.3 Synthesis of (E)-2-(Fur-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoic acid

Prepare by a method similar to Example 3.3 using(E)-2-(fur-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoicacid to give the title compound: mp; 223-225° C. (dec). ¹H NMR (DMSO-d₆)δ 13.0 (bs, 2H), 12.35 (s, 1H), 7.94 (s, 1H), 7.48 (m, 1H), 7.42 (d, 1H,J=1.7 Hz), 7.34 (m, 1H), 7.15 (d,1H, J=1.7 Hz), 5.77 (m, 1H).

EXAMPLE 5 Preparation of(E)-2-(Pyrid-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid 5.1 Synthesis of(Z)-2-(Pyrid-3-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile

Combine 2-carboethoxy-4,6-dichloroindole (1.43 g, 5.0 mmol),pyrid-3-ylacetonitrile (0.59 g, 5.0 mmol), piperidine (0.2 mL), andethanol (30 mL). Heat to reflux. After 16 hours, cool to ambienttemperature. Add diethyl ether to give a solid. Filter, rinse withdiethyl ether, dry, recrystallize from acetone/water, filter, and dry togive the title compound: mp; 233-234° C. (dec). ¹H NMR (DMSO-d6) δ 12.41(br s, 1H), 8.86 (s, 1H), 8.57 (d, 1H, J=1 Hz), 8.16 (s, 1H), 7.94 (d,1H, J=6.1 Hz), 7.41-7.36 (m, 1H), 7.41 (s, 1H), 7.06 (m, 1H), 4.30 (q,2H, J=7.05 Hz), 1.23 (t, 3H, J=7.05 Hz).

5.2 Synthesis of(Z)-2-(Pyrid-3-yl)-3-(4,6dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide

Combine(Z)-2-(pyrid-3-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile(0.5 g, 1.3 mmol), sulfuric acid (6 mL), acetic acid (6 mL), and water(0.3 mL). Heat to about 80° C. After 16 hours, pour the reaction mixtureonto water to give a solid. Filter the solid and combine with lithiumhydroxide (91.0 mg, 2.6 mmol) in tetrahydrofuran/water (1/1, 10 mL) andheat to 60° C. After 16 hours, filter the solid and recrystallize fromacetone/water give the title compound. 1H NMR (300 MHz, DMSO-d₆) δ 13.25(s, 1H, NH), 11.92 (s, 1H, NH), 8.66 (m, 1H), 8.57 (m, 1H), 8.43 (s,1H), 7.91 (m, 1H), 7.57 (s, 1H), 7.45 (s overlapping m, 2H).

5.3 Synthesis of(E)-2-(Pyrid-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid

Combine (Z)-2-(pyrid-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylicacid)propenoic acid imide (152 mg, 0.43 mmol), aqueous 6 M sodiumhydroxide solution (6 mL), and tetrahydrofuran (2 mL). Heat to 60° C.After 48 hours, cool the reaction mixture to ambient temperature andevaporate in vacuo to remove the tetrahydrofuran. Dilute the reactionmixture with water (20 mL) and acidify to pH 2 with aqueous 12 Mhydrochloric acid solution to give a solid. Filter, rise with water, anddry to give the title compound: mp 285-286° C. (dec). ¹H NMR (300 MHz,DMSO-d₆) δ 13.18 (br m, 2H), 12.28 (s, 1H), 8.26 (m, 1H), 8.22 (s, 1H),8.09 (m, 1H), 7.39 (d, 1H, J=1.8 Hz), 7.35 (s, 1H), 7.19 (s overlappingm, 2H).

EXAMPLE 6 Preparation of(E)-2-(Pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid 6.1 Synthesis of(Z)-2-(Pyrid-2-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile

Combine 2-carboethoxy-4,6-dichloroindole (1.43 g, 5.0 mmol),pyrid-2-ylacetonitrile (0.59 g, 5.0 mmol), piperidine (0.2 mL), andethanol (30 mL). Heat to reflux. After 16 hours, cool to ambienttemperature. Add diethyl ether to give a solid. Filter, rinse withdiethyl ether, dry, recrystallize from acetone/water, filter, and dry togive the title compound: mp; 250-254° C. (dec). ¹H NMR (DMSO-d₆) δ 12.9(br s, 1H), 8.86 (s, 1H), 8.70 (d, 1H, J=1 Hz), 8.00 (m, 1H), 7.82 (d,1H, J=7.2 Hz), 7.55 (s, 1H), 7.48 (m, 1H), 7.48 (m, 1H), 7.34 (s, 1H),4.35 (q, 2H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz).

6.2 Synthesis of(Z)-2-(Pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide

Combine(Z)-2-(pyrid-2-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile(1.0 g, 2.6 mmol), sulfuric acid (15 mL), acetic acid (15 mL), and water(0.3 mL). Heat to about 80° C. After 16 hours, cool to ambienttemperature and pour the reaction mixture into water (50 mL) to obtain asolid. Filter the solid, rinse with water. Recrystallize fromacetone/water, filter, and dry to give the title compound as thesulfuric acid salt: mp; >300° C. ¹H NMR (DMSO-d₆) δ 13.47 (br s, 1H),12.14 (m, 1H), 8.90-8.83 (m, 1H), 8.83 (s, 1H), 8.02 (d, 1H, J=7.7 Hz),7.81 (m, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.48 (m, 1H), 7.34 (s, 1H).

Combine (Z)-2-(pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylicacid)propenoic acid imide sulfuric acid salt (285 mg, 0.65 mmol),lithium hydroxide (67 mg, 1.6 mmol), and tetrahydrofuran/water (1/1, 10mL). Heat at 60° C. After 16 hours, filter, rinse with water, and dry togive the title compound.

6.3 Synthesis of(E)-2-(Pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid

Prepare by a method similar to Example 5.3 using(Z)-2-(pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide (0.5 g, 1.3 mmol) to give the title compound.

EXAMPLE 7 Preparation of(E)-2-(Pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid 7.1 Synthesis of(Z)-2-(Pyrid-4-yl)-3-(2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrile

Prepare by a method similar to Example 5.1 using pyrid-4-ylacetonitrilehydrochloride salt and triethylamine to give the title compound: mp;265° C. (dec). ¹H NMR (DMSO-d₆) δ 11.97 (br s, 1H), 8.74 (m, 3H), 7.76(d, 2H, J=4.7 Hz), 7.56 (s, 1H), 7.39 (m, 1H), 4.35 (q, 2H, J=6.8 Hz),1.24 (t, 3H, J=6.8 Hz).

7.2 Synthesis of(Z)-2-(Pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide

Prepare by a method similar to Example 5.2 using(Z)-2-(pyrid-4-yl)-2-carboethoxy-4,6-dichloroindol-3-yl)propenonitrileto give the title compound.

7.3 Synthesis of(E)-2-(Pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid

Prepared by a method similar to Example 5.3 using(Z)-2-(pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide to give the title compound.

EXAMPLE 8 Preparation of(E)-2-(Thien-2-yl)-3-methyl-3-(indol-3-yl-2-carboxylic acid)propenoicacid 8.1 Synthesis of(E)-2-(Thien-2-yl)-3-methyl-3-(1-p-toluenesulfonyl-2-carboethoxy-indol-3-yl)propenoicacid, t-butyl ester

Prepare by the method of Example 2.1 using(Z)-2-bromo-3-methyl-3-(1-p-toluenesulfonyl-2-carboethoxy-indol-3-yl)propenoicacid, t-butyl ester to give the title compound.

8.2 Synthesis of(E)-2-(Thien-2-yl)-3-methyl-3-(1-p-toluenesulfonyl-2-carboethoxy-indol-3-yl)propenoicacid

Prepare by the method of Example 2.2 using(E)-2-(thien-2-yl)-3-methyl-3-(1-p-toluenesulfonyl-2-carboethoxy-indol-3-yl)propenoicacid, t-butyl ester to give the title compound.

8.3 Synthesis of (E) and(Z)-2-(Thien-2-yl)-3-methyl-3-(indol-3-yl-2-carboxylic acid)propenoicacid

Prepare by the method of Example 2.3 using (E) and(Z)-2-(thien-2-yl)-3-methyl-3-(1-p-toluenesulfonyl-2-carboethoxy-indol-3-yl)propenoicacid to give the title compound.

The compounds of Formula (I) are excitatory amino acid antagonists. Theyantagonize the effects which excitatory amino acids have upon the NMDAreceptor complex. They preferentially bind to the strychnine-insensitiveglycine binding site on the NMDA receptor complex associated with thetreatment of a number of disease states. See Palfreyman, M. G. and B. M.Baron, Excitatory Amino Acid Antagonists, B. S. Meldrum ed., BlackwellScientific, 101-129 (1991); and, Kemp, J. A., and P. D. Leeson, Trendsin Pharmacological Sciences, 14, 20-25 (1993).

Affinity for brain strychnine-insensitive glycine binding site on theNMDA receptor complex can be determined in the following way.Approximately 50 to 60 young male Sprague-Dawley rats (C-D strain), aresacrificed by decapitation and their cerebral cortices and hippocampiare removed. The two brain regions are combined and homogenized in 15volumes of ice-cold 0.32 M sucrose using a teflon glass homogenizer (10passes at 400 rpm). The homogenates are centrifuged at 1000×g for 10minutes and the supernatants are transferred and recentrifuged at44,000×g for 20 minutes. The upper white part of the pellets areresuspended with a pipet in ice-cold water and homogenized with apolytron (setting 6 for 10 seconds) and centrifuged at 44,000×g for 15minutes. Pellets are then resuspended in 6 volumes of water and placedin a dry-ice/methanol bath until frozen, followed by thawing at 37° C.in a shaking water bath. The freeze/thaw process is repeated and finalvolumes of the suspensions adjusted to 15 volumes with water andcentrifuged at 44,000×g for 15 minutes. The resulting pellets areresuspended in 15 volumes of 10 mM HEPES-KOH(N-2-hydroxyethyl-piperazine-N′-2-ethanesulsonic acid—potassiumhydroxide) at pH 7.4 containing 0.04% Triton X-100 (v/v), incubated at37° C. for 15 minutes and centrifuged at 44,000×g for 15 minutes. Thepellets are then resuspended in 15 volumes of 10 mM HEPES-KOH at pH 7.4with a polytron (setting of 6 for 10 seconds) and centrifuged at44,000×g for 15 minutes. Repeat this resuspension/centrifugation processan additional 2 times. The membranes are then resuspended in 3 volumesof 10 mM HEPES and stored frozen at −80° C.

When the assay is to be performed, the membranes are thawed at ambienttemperature and diluted with 9 volumes of 10 mM HEPES-KOH pH 7.4 andincubated at 25° C. for 15 minutes This is followed by centrifugation at44,000×g for 15 minutes then resuspension with 10 mM HEPES-KOH at pH 7.4using a polytron. The incubation/resuspension/centrifugation process isrepeated an additional 2 times and the final pellet is resuspended in 6volumes of 50 mM HEPES-KOH at pH 7.4. Incubation vials in triplicate,receive 50 μL of 200 nM [³H]-glycine, 50 μL of 1000 nM strychnine, 50 μLof various concentrations of test compounds diluted with 50 mM HEPES-KOHat pH 7.4, and 200 μL of membrane suspension (400 μg protein/aliquot) ina final volume of 0.5 mL. Incubations are carried out at 4° C. for 30minutes and are terminated by centrifugation at 46,000×g for 10 minutes.The supernatants are decanted and the pellets are rinsed rapidly with 2mL of ice-cold 50 mM HEPES-KOH at pH 7.4, then dissolved in 4 mL ofReady Protein (Beckman Instruments) and counted by liquid scintillationspectrometry.

Specific binding of [³H]-glycine is measured as the total radioactivitybound minus that bound to the receptors in the presence of 0.1 mM MD-serine. Total membrane-bound radioactivity is less that 2% of thatadded to the assay vials. Since these conditions limit the total bindingto less than 10% of the radioactivity, the concentration of free liganddoes not change appreciably during the assay. The results of this assayare expressed as an IC₅₀, that is the molar concentration of a compoundwhich causes 50% inhibition of ligand binding.

Binding to the strychnine- insensitive glycine binding site on the NMDAreceptor Compound No. complex, IC₅₀, 1 5.25 2 9.0 3 22 4 21 Compound No.1 is the compound of Example 1, (E) and(Z)-2-(Thien-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid; Compound No. 2 is the compound of Example 2, (E) and(Z)-2-(Thien-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid; Compound No. 3 is the compound of Exampie 3, (E) and(Z)-2-(Fur-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid; Compound No. 3 is the compound of Example 3, (E) and(Z)-2-(Fur-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid.

The compounds exhibit anticonvulsant properties and are useful in thetreatment of grand mal seizures, petit mal seizures, psychomotorseizures, autonomic seizures, etc. One method of demonstrating theirantiepileptic properties is by their ability to inhibit the seizuresthat are caused by the administration of quinolinic acid. This test canbe conducted in the following manner.

One group containing ten mice are administered 0.01-100 micrograms oftest compound intracerebroventricularly in a volume of 5 microliters ofsaline. A second control group containing an equal number of mice areadministered an equal volume of saline as a control. Approximately 5minutes later, both groups are administered 7.7 micrograms of quinolinicacid intracerebroventricularly in a volume of 5 microliters of saline.The animals are observed for 15 minutes thereafter for signs of tonicseizures. The control group will have a statistically higher rate oftonic seizures than will the test group.

Another method of demonstrating the antiepileptic properties of thesecompounds is by their ability to inhibit audiogenic convulsions inDBA/2J mice. This test can be conducted in the following manner.Typically one group of from 6-8 male DBA/2J audiogenic mice areadministered from about 0.01 micrograms to about 10 micrograms of thetest compound into the lateral ventricle of the brain or from about 0.1milligrams to about 300 milligrams intraperitoneally. A second group ofmice are administered an equal volume of a saline control by the sameroute. Five minutes to 4 hours later, the mice are placed individuallyin glass jars and are exposed to a sound of 110 decibels for 30 seconds.Each mouse is observed during the sound exposure for signs of seizureactivity. The control group will have a statistically higher incidenceof seizures than the group which receives the test compound.

The compounds of Formula (I) are useful for preventing or minimizing thedamage which nervous tissues contained within the CNS suffer uponexposure to either ischemic, traumatic, or hypoglycemic conditionsincluding strokes or cerebrovascular accidents, cardiovascular surgery,concussions, hyperinsulinemia, cardiac arrest, drownings, suffocations,and neonatal anoxic trauma. The compounds should be administered to thepatient within 24 hours of the onset of the hypoxic, ischemic,traumatic, or hypoglycemic condition in order to minimize the CNS damagewhich the patient will experience.

The compounds of Formula (I) minimize or prevent CNS damage afterischemia. These anti-ischemia properties can be demonstrated by theability of the compounds of Formula (I) to reduce infarct volume in ratssubjected to middle cerebral artery occlusion as follows. MaleSprague-Dawley rats are subjected to occlusion of the middle cerebralartery by an adaptation of the method of H. Memezawa et al., IschemiaPenumbra in a Model of Reversible Middle Cerebral Artery Occlusion inthe Rat, Experimental Brain Research, 89, 67-78 (1992). The rat isanesthetized with halothane in a mixture of O₂ and NO (1:2 ratio) and amidline incision is made in the ventral neck region. An indwellingvenous catheter is placed in the jugular vein. Under a dissectingmicroscope, the left common carotid artery is identified at itsbifurcation into the external carotid artery and internal carotidartery. Two ties are placed on the external carotid artery. The internalcarotid artery is exposed distally to the point of its bifurcation intothe intracranial internal carotid artery and the pterygopalatine artery.A small cut is made in the distal segment of the external carotid arteryand a 3-0 nylon monofilament is introduced into the lumen of theexternal carotid artery. The two previously placed ties are tightenedaround the monofilament. The external carotid artery is cut andreflected caudally so that the monofilament can be advanced into theinternal carotid artery, past the distal internal carotidartery/pterygopalatine artery bifurcation and continuing into theintranial segment of the internal carotid artery to a distance of 20 mm,at which point the origin of the middle cerebral artery is occluded. Theties are then tightened and the wound is closed. Compound or vehiclealone is administered intravenously at a pre-determined timepost-ischemia and dosing can be single, multiple, or by continuousinfusion.

Animals are given food and water and allowed to survive for 24 h. Priorto sacrifice, the rat is weighed and given a battery of fourneurological tests to measure muscle strength, grooming skills, posturalreflexes and sensorimotor integration, as described by C. G. Markgraf etal., Sensorimotor and Cognitive Consequences of Middle Cerebral ArteryOcclusion in Rats, Brain Research, 575, 238-246 (1992). The animal isthen decapitated, the brain is removed, sliced into six sections andincubated in 2% 2,3,5-triphenyltetrazolium chloride for 30 minutes, asdescribed by K. Isayama et al., Evaluation of 2,3,5-TriphenyltetrazoliumChloride Stains to Delineate Rat Brain Infarcts, Stroke 22, 1394-1398(1991). The area of infarction is clearly visible. Infarct area isdetermined by computer-assisted image analysis for each of the sixsections and integrated over the anterior-posterior extent of the brainto yield infarct volume. Group means±SE are determined for infarctvolume and for the four behavioral tests and compared for the groupsusing ANOVA with orthogonal contrasts.

Another method of demonstrating the ability of the compounds of Formula(I) minimize or prevent CNS damage after ischemia is as follows: Anadult male rat weighing 200-300 g is anesthetized with halothane in amixture of O₂ and NO (1:2 ratio) and a midline incision is made in theventral neck region. An indwelling venous catheter is placed in thejugular vein. The common carotid artery is exposed and dissected freefrom the vagus and cervical sympathetic nerves. One 4-0 silk sutureligature is tied securely. The animal is the placed in a restraint sothat the right side of the head is facing up. The area is rubbed withbetadiene and then the incision through the skin and the temporalismuscle is made in order to expose the skull. Care should be taken no tocut the lagre vein that is visible through the muscle. Once the skull isexposed the middle carotid artery is visible through the skull. Using aForedom micro drill with a 4 mm burr bit, a small (approximately 8 mm)hole is made in the skull directly above the middle carotid artery.After drilling through the skull there is usually a thin layer of skullremaining that is carefully removed with fine foreceps. Remove the dura,as required, away from the area directly above the middle carotidartery. The right middle cerebral artery occlusion is then performed byelectrocoagulation without damaging the brain. The middle cerebralartery is cauterized immediately distal to the inferior cortical vein. Asmall piece of foam gel is then placed in the area and the muscle andskin in sutured with 3-0 silk. Compound or vehicle alone is administeredintravenously at a predetermined time post-ischemia and dosing can besingle, multiple, or by continuous infusion.

Animals are given food and water and allowed to survive for 24 h. Theanimal is then decapitated, the brain is removed, sliced into sixsections and incubated in 2% 2,3,5-triphenyltetrazolium chloride for 30minutes, as described by K. Isayama et al., Evaluation of2,3,5-Triphenyltetrazolium Chloride Stains to Delineate Rat BrainInfarcts, Stroke 22, 1394-1398 (1991). The area of infarction is clearlyvisible. Infarct area is determined by computer-assisted image analysisfor each of the six sections and integrated over the anterior-posteriorextent of the brain to yield infarct volume. Group means±SE aredetermined for infarct volume and for the four behavioral tests andcompared for the groups using ANOVA with orthogonal contrasts.

The compounds are also useful in the treatment of neurodegenerativediseases such as Huntington's disease, Alzheimer's disease, seniledementia, glutaric acidaemia type I, multi-infarct dementia, amyotrophiclateral sclerosis, and neuronal damage associated with uncontrolledseizures. The administration of these compounds to a patientexperiencing such a condition will serve to either prevent the patientfrom experiencing further neurode-generation or it will decrease therate at which the neurodegeneration occurs.

As is apparent to those skilled in the art, the compounds will notcorrect any CNS damage that has already occurred as the result of eitherdisease, physical injury, or a lack of oxygen or sugar. As used in thisapplication, the term “treat” refers to the ability of the compounds toprevent further damage or delay the rate at which any further damageoccurs.

The compounds exhibit an anxiolytic effect and are thus useful in thetreatment of anxiety. These anxiolytic properties can be demonstrated bytheir ability to block distress vocalizations in rat pups. This test isbased upon the phenomenon that when a rat pup is removed from itslitter, it will emit an ultrasonic vocalization. It was discovered thatanxiolytic agents block these vocalizations. The testing methods havebeen described by Gardner, C. R., Distress Vocalization in Rat Pups: ASimple Screening Method For Anxiolytic Drugs, J. Pharmacol. Methods, 14,181-87 (1986) and Insel et.al., Rat Pup Isolation Calls: PossibleMediation by the Benzodiazepine Receptor Complex, Pharmacol. Biochem.Behav., 24, 1263-67 (1986).

The compounds also exhibit an analgesic effect and are useful incontrolling pain. The compounds are also effective in the treatment ofmigraine.

In order to exhibit these therapeutic properties, the compounds need tobe administered in a quantity sufficient to inhibit the effect which theexcitatory amino acids have upon the NMDA receptor complex. The dosagerange at which these compounds exhibit this antagonistic effect can varywidely depending upon the particular disease being treated, the severityof the patient's disease, the patient, the particular compound beingadministered, the route of administration, and the presence of otherunderlying disease states within the patient, etc. Typically aneffective dose of the compounds will range of from about 0.1 mg/kg/dayto about 50 mg/kg/day for any of the diseases or conditions listedabove. Repetitive daily administration may be desirable and will varyaccording to the conditions outlined above.

The compounds of the present invention may be administered by a varietyof routes. They are effective if administered orally. The compounds mayalso be administered parenterally (i.e. subcutaneously, intravenously,intramuscularly, intraperitoneally, or intrathecally).

Pharmaceutical compositions can be manufactured utilizing techniquesknown in the art. Typically a therapeutic amount of the compound will beadmixed with a pharmaceutically acceptable carrier.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, lozenges, melts,powders, suspensions, or emulsions. Solid unit dosage forms can becapsules of the ordinary gelatin type containing, for example,surfactants, lubricants and inert fillers such as lactose, sucrose, andcornstarch or they can be sustained release preparations.

In another embodiment, the compounds of Formula (I) can be tableted withconventional tablet bases such as lactose, sucrose, and cornstarch, incombination with binders, such as acacia, cornstarch, or gelatin,disintegrating agents such as potato starch or alginic acid, and alubricant such as stearic acid or magnesium stearate. Liquidpreparations are prepared by dissolving the active ingredient in anaqueous or nonaqueous pharmaceutically acceptable solvent which may alsocontain suspending agents, sweetening agents, flavoring agents, andpreservative agents as are known in the art.

For parenteral administration the compounds may be dissolved in aphysiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Illustrative of suitablepharmaceutical carriers are water, saline, dextrose solutions, fructosesolutions, ethanol, or oils of animal, vegetative, or synthetic origin.The pharmaceutical carrier may also contain preservatives, buffers,etc., as are known in the art. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid as isknown in the art.

The compounds of this invention can also be administered topically. Thiscan be accomplished by simply preparing a solution of the compound to beadministered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or withoutother excipients. Preferably topical administration will be accomplishedusing a patch either of the reservoir and porous membrane type or of asolid matrix variety.

Some suitable transdermal devices are described in U.S. Pat. Nos.3,742,951; 3,797,494; 3,996,934; and 4,031,894. These devices generallycontain a backing member which defines one of its face surfaces, anactive agent permeable adhesive layer defining the other face surfaceand at least one reservoir containing the active agent interposedbetween the face surfaces. Alternatively, the active agent may becontained in a plurality of microcapsules distributed throughout thepermeable adhesive layer. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

In another device for transdermally administering the compounds inaccordance with the present invention, the pharmaceutically activecompound is contained in a matrix from which it is delivered in thedesired gradual, constant and controlled rate. The matrix is permeableto the release of the compound through diffusion or microporous flow.The release is rate controlling. Such a system, which requires nomembrane is described in U.S. Pat. No. 3,921,636. At least two types ofrelease are possible in these systems. Release by diffusion occurs whenthe matrix is nonporous. The pharmaceutically effective compounddissolves in and diffuses through the matrix itself. Release bymicroporous flow occurs when the pharmaceutically effective compound istransported through a liquid phase in the pores of the matrix.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart.

As used in this application:

aa) the “patient” refers to warm blooded animals such as, for exampleguinea pigs, mice, rats, cats, rabbits, dogs, monkeys, chimpanzees, andhuman;

bb) the term “treat” refers to the ability of the compounds to eitherrelieve, alleviate, or slow the progression of the patient's disease;

cc) the term “neurodegeneration” refers to a progressive death anddisappearance of a population of nerve cells occurring in a mannercharacteristic of a particular disease state and leading to braindamage.

The compounds of Formula (I) may also be admixed with any inert carrierand utilized in laboratory assays in order to determine theconcentration of the compound within the serum, urine, etc., of thepatient as is known in the art.

Neurodegenerative diseases are typically associated with a loss of NMDAreceptors. Thus, the compounds of Formula (I) may be utilized indiagnostic procedures to aid physicians with the diagnosis ofneurodegenerative diseases. The compounds may be labeled with imagingagents known in the art such as isotopic ions and administered to apatient in order to determine whether the patient is exhibiting adecreased number of NMDA receptors and the rate at which that loss isoccurring.

What is claimed is:
 1. A compound selected from the group consisting of(Z)-2-(Pyrid-3-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide, (Z)-2-(Pyrid-2-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylicacid)propenoic acid imide, and(Z)-2-(Pyrid-4-yl)-3-(4,6-dichloroindol-3-yl-2-carboxylic acid)propenoicacid imide.